The present invention relates to seco-baccatin III derivatives.
Taxane-skeleton diterpenes, in particular Paclitaxel and Docetaxel, are at present used in medicine for the treatment of tumors of different origin.
However, the presently available taxane derivatives have remarkable side effects and also quickly induce resistance, analogously to other antitumor drugs.
The present invention relates to derivatives of seco-baccatine III, which is disclosed in U.S. Pat. No. 5,756,776, characterized by bioavailability through the oral route, reduced toxicity and extremely high antiangiogenetic activity.
The compounds of the present invention have the following general formula (I): 
wherein
R and R1, which can be the sane or different, are hydrogen, a C1-C18 acyl group, an optionally substituted aroyl group or a xe2x80x94CONR6R7 wherein R6 and R7, which can be the same or different, are C1-C4 alkyl, benzyl, or phenyl groups;
R2 is hydrogen or forms with R3 a carbonate or thiocarbonate residue;
R3 is hydrogen, xe2x80x94OR5 group, wherein R5 is hydrogen, or it forms with R2 a carbonate or thiocarbonate residue;
R4 is a benzoyl group optionally substituted at the meta-position, or a hetaroyl group;
R1 is hydrogen or a C1-C4 alkyl group;
R11 is a C1-C4 alkyl, a C2-C6 alkenyl, aryl or hetaryl;
R111 is a C1-C4 alkyl, C1-C18 acyl, aryl group or tert-butoxy group, with the proviso that R and R1 cannot be both hydrogen.
A C1-C18 acyl group is preferably a formyl, acetyl, n-propanoyl, n-hexanoyl group.
An optionally substituted aroyl group is preferably benzoyl, optionally substituted with one or three substituents selected from halogen atoms or C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano, nitro groups.
A meta-substituted benzoyl group is preferably a 3-halo-benzyl or 3-methoxybenzoyl group.
A hetaroyl group is preferably a 5- or 6-membered heteroaryl having one or two oxygen, nitrogen or sulfur atoms in the ring and substituted with a carbonyl group, for example 2- or 3-thenoyl, nicotinoyl, 2- or 3-furoyl.
Aryl is preferably phenyl and hetaryl is preferably 2- or 3-furyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl.
A preferred group of compounds of formula (I) is that in which:
R and R1, which are the same, are a C1-C18 acyl group, an optionally substituted benzoyl group as defined above or a CONR6R7 group, more preferably R and R1 are acetyl or 3,4,5-trimethoxy-benzoyl;
R2 is hydrogen;
R3 is hydrogen;
R4 is benzoyl;
Rxe2x80x2 is hydrogen or methyl;
Rxe2x80x3 is C1-C4 alkyl or C2-C6 alkenyl, more preferably isobutyl or isobutenyl;
Rxe2x80x2xe2x80x3 is a tert-butoxy group.
A further group of preferred compounds is the one in which R is hydrogen and R1 is an acyl, aroyl or CONR6R7 group as defined above, R2 and R3 are hydrogen, R4 is benzoyl, R1 is hydrogen or methyl, Rxe2x80x3 is C1-C4 alkyl or C2-C6 alkenyl and Rxe2x80x2xe2x80x3 is tert-butoxy.
The esterification of the hydroxyls at C-7 and C-9 induces, compared with known compounds, an increase in the cytotoxic activity on the resistant cell lines as well as improved absorption through the oral route. The compounds of the invention are less potent than Paclitaxel, taken as the reference drug, in binding with tubulin, while keeping comparable cytotoxicity on the sensitive cancer lines. These compounds mainly differ from those of the prior art in the antiangiogenetic activity. Table shows the in vivo activity of some C-seco-10-dehydro-10-deacetyl-7,9-bisacetyl-baccatine III and C-seco-10-dehydro-10-deacetyl-7,9-bisacetyl-1,14-carbonate-baccatine III derivatives having the same isoserine chain.
The antiangiogenic activity was evaluated by means of the Matrigel test, in which angiogenesis is induced by FGF-2 (150 mg/pellet) adsorbed on a Matrigel pellet (12.5 mg/ml, 0.5 mL) injected subcutaneously in C57BL6N mice.
The tested compound was administered through the oral route daily or through the intraperitoneal route on alternate days, at the shown concentration. After 7 days, the angiogenic response was evaluated by measuring the hemoglobin content in the pellets, according to the procedure by Drabkin.
The compounds of the invention are prepared by reacting C-seco-10-dehydro-10-deacetyl-7,9-hydroxy baccatine III described in U.S. Pat. No. 5,756,776 with a carboxylic acid reactive derivative (chloride or anhydride), according to known acylation methods.
The C7 and C9 diesters can be prepared by using at least two equivalents of the reactive derivative. The carbamate groups can be introduced with conventional methods, for example by reaction with phosgene and an amine of formula R6R7NH.
The resulting compounds are then reacted, according to known procedures, with an isoserine derivative, usually an oxazolidine derivative, which, by acid treatment under mild conditions gives compounds (I).
The compounds of the invention are characterized by low systemic toxicity: at doses effective in inhibiting the tumor growth they induce neither weight loss nor evident neurotoxicity; in the nude mouse transplanted with human tumor cells, a dose of Paclitaxel, used as the reference drug, exerting the same antitumor activity, also induces tremors and weight loss up to 20%.
The compounds of the present invention, thanks to their high water solubility, can be easily formulated in injectable preparations.
Compounds (I) can also be formulated in the form of conventional oral compositions (capsules or tablets).
Thanks to their low toxicity, compounds (I) can be administered intravenously at dosages up to 600 mg/m2 and orally at dosages up to 1000 mg/m2. Dosages can be decreased to 50 mg/m2 in the treatment of rheumatoid arthritis.
The following examples further illustrate the invention without limiting its scope.